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Science 292 (5516): 468-472

Copyright © 2001 by the American Association for the Advancement of Science

Targeting of HIF-alpha to the von Hippel-Lindau Ubiquitylation Complex by O2-Regulated Prolyl Hydroxylation

Panu Jaakkola,1* David R. Mole,1* Ya-Min Tian,1 Michael I. Wilson,1 Janine Gielbert,2 Simon J. Gaskell,2 Alexander von Kriegsheim,3 Holger F. Hebestreit,3 Mridul Mukherji,4 Christopher J. Schofield,4 Patrick H. Maxwell,1dagger ‡ Christopher W. Pugh,1dagger ‡ Peter J. Ratcliffe1dagger ddagger

Hypoxia-inducible factor (HIF) is a transcriptional complex that plays a central role in the regulation of gene expression by oxygen. In oxygenated and iron replete cells, HIF-alpha subunits are rapidly destroyed by a mechanism that involves ubiquitylation by the von Hippel-Lindau tumor suppressor (pVHL) E3 ligase complex. This process is suppressed by hypoxia and iron chelation, allowing transcriptional activation. Here we show that the interaction between human pVHL and a specific domain of the HIF-1alpha subunit is regulated through hydroxylation of a proline residue (HIF-1alpha P564) by an enzyme we have termed HIF-alpha prolyl-hydroxylase (HIF-PH). An absolute requirement for dioxygen as a cosubstrate and iron as cofactor suggests that HIF-PH functions directly as a cellular oxygen sensor.

1 The Henry Wellcome Building of Genomic Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
2 Michael Barber Centre for Mass Spectrometry, Department of Chemistry, University of Manchester Institute of Science and Technology, Manchester M60 1QD, UK.
3 Glycobiology Institute, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
4 The Oxford Centre for Molecular Sciences and The Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QY, UK.
*   These authors contributed equally to the work.

dagger    The contribution of the three senior authors was equivalent.

ddagger    To whom correspondence should be addressed. E-mail: peter.ratcliffe{at}, cwpugh{at}, pmaxwell{at}

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Statin inhibits hypoxia-induced endothelin-1 via accelerated degradation of HIF-1{alpha} in vascular smooth muscle cells.
T. Hisada, M. Ayaori, N. Ohrui, H. Nakashima, K. Nakaya, H. Uto-Kondo, E. Yakushiji, S. Takiguchi, Y. Terao, Y. Miyamoto, et al. (2012)
Cardiovasc Res 95, 251-259
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Adaptive and Maladaptive Cardiorespiratory Responses to Continuous and Intermittent Hypoxia Mediated by Hypoxia-Inducible Factors 1 and 2.
N. R. Prabhakar and G. L. Semenza (2012)
Physiol Rev 92, 967-1003
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The HIF-1{alpha} Hypoxia Response in Tumor-Infiltrating T Lymphocytes Induces Functional CD137 (4-1BB) for Immunotherapy.
A. Palazon, I. Martinez-Forero, A. Teijeira, A. Morales-Kastresana, C. Alfaro, M. F. Sanmamed, J. L. Perez-Gracia, I. Penuelas, S. Hervas-Stubbs, A. Rouzaut, et al. (2012)
Cancer Discovery 2, 608-623
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Loss of Fibroblast HIF-1{alpha} Accelerates Tumorigenesis.
J.-w. Kim, C. Evans, A. Weidemann, N. Takeda, Y. S. Lee, C. Stockmann, C. Branco-Price, F. Brandberg, G. Leone, M. C. Ostrowski, et al. (2012)
Cancer Res. 72, 3187-3195
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State of the Science: An Update on Renal Cell Carcinoma.
E. Jonasch, P. A. Futreal, I. J. Davis, S. T. Bailey, W. Y. Kim, J. Brugarolas, A. J. Giaccia, G. Kurban, A. Pause, J. Frydman, et al. (2012)
Mol. Cancer Res. 10, 859-880
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Inhibition of {alpha}-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors.
M. Xiao, H. Yang, W. Xu, S. Ma, H. Lin, H. Zhu, L. Liu, Y. Liu, C. Yang, Y. Xu, et al. (2012)
Genes & Dev. 26, 1326-1338
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Targets and delivery methods for therapeutic angiogenesis in peripheral artery disease.
G. O. Ouma, R. A. Jonas, M. H. U. Usman, and E. R. Mohler III (2012)
Vascular Medicine 17, 174-192
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Agents That Stabilize Mutated von Hippel-Lindau (VHL) Protein: Results of a High-Throughput Screen to Identify Compounds That Modulate VHL Proteostasis.
Z. Ding, P. German, S. Bai, Z. Feng, M. Gao, W. Si, M. M. Sobieski, C. C. Stephan, G. B. Mills, and E. Jonasch (2012)
J Biomol Screen 17, 572-580
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Iron sensing and signalling.
R. Evstatiev and C. Gasche (2012)
Gut 61, 933-952
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The updated biology of hypoxia-inducible factor.
S. N. Greer, J. L. Metcalf, Y. Wang, and M. Ohh (2012)
EMBO J. 31, 2448-2460
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Hypoxia-Inducible Factor-2{alpha} Activation Promotes Colorectal Cancer Progression by Dysregulating Iron Homeostasis.
X. Xue, M. Taylor, E. Anderson, C. Hao, A. Qu, J. K. Greenson, E. M. Zimmermann, F. J. Gonzalez, and Y. M. Shah (2012)
Cancer Res. 72, 2285-2293
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JMJD5, a Jumonji C (JmjC) Domain-containing Protein, Negatively Regulates Osteoclastogenesis by Facilitating NFATc1 Protein Degradation.
M.-Y. Youn, A. Yokoyama, S. Fujiyama-Nakamura, F. Ohtake, K.-i. Minehata, H. Yasuda, T. Suzuki, S. Kato, and Y. Imai (2012)
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